Creutzfeldt-Jakob disease (CJD) is a progressive, fatal neurologic disease of humans due to a slow virus-like (prion) infectious agent. A confirmatory (i.e., hypothesis testing) case-control study of Creutzfeldt- Jakob disease is proposed to evaluate specific etiologic and transmission hypotheses generated from the three (small) previous case-control studies conducted worldwide. One of these studies was conducted by the PI of this proposal. Specifically, the hypotheses generated concerning certain iatrogenic exposures, trauma, and zoonosis through contact or ingestion of animal tissue will be investigated. The study will collect information on 100 CJD cases and 200 matched controls. One to two hundred case- surrogates, the 200 controls, and 200-400 control-surrogates will be interviewed. Random digit dialing will be used as the method of selection of controls, thus matching for residential location. Other matching criteria are year of birth (+ 5 years), sex and race. To confirm and classify the diagnosis of CJD, medical records will be reviewed, two blinded expert electroencephalographers will read EEGs, and a blinded expert neuropathologist will determine histology. This will insure that the study's diagnostic criteria are met. Demographic data, animal exposure, dietary and past medical histories, and other selected data will be obtained using a structured questionnaire by telephone interview. Matched case-control conditional logistic regression analysis with stepwise inclusion of factors and interactions will be undertaken. The proposed study differs from previous case-control studies on CJD in : 1) its confirmatory nature; 2) inclusion of a larger case series from various regions in the US, allowing more meaningful statistical conclusions as well as more sophisticated statistical analyses; 3) improved methodology, e.g.; random digit dialing (controls should be more representative of the general populations than the controls used in previous studies (hospital patients and friends); and 4) a more focussed questionnaire. Identification of risk factors and subsequent interruption of the chain of transmission should prevent most new cases of this untreatable and invariably fatal dementia.